Use of pbo-peo-pbo block copolymers in ophthalmic compositions

ABSTRACT

The use of poly(oxybutylene)-poly(oxyethylene)-poly(oxybutylene) block copolymers in pharmaceutical compositions useful, for modifying the surfaces of contact lenses and other medical devices is disclosed. The present invention is based in-part on a discovery that this class of compounds is particularly efficient in wetting hydrophobic surfaces, such as the surfaces of silicone hydrogel contact lenses and other types of ophthalmic lenses, but do not induce foaming when used in conjunction with a peroxide-based contact lens disinfection regimen. Such compounds may also be useful for cleaning purposes. The use of the compounds as surfactants in peroxide-based compositions for disinfecting contact lenses therefore represents a preferred embodiment of the present invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. §119 to U.S.Provisional Patent Application No. 61/350,787, filed Jun. 2, 2010, theentire contents of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention is directed to ophthalmic compositions containingone or more block copolymers referred to as(polyoxybutylene)-(polyoxyethylene)-(polyoxybutylene) block copolymers(“PBO-PEO-PBO”). The invention is particularly directed to the use ofPBO-PEO-PBO block copolymers as non-foaming wetting agents inperoxide-based compositions for disinfecting contact lenses.

BACKGROUND OF THE INVENTION

Disinfecting compositions are frequently used in conjunction with theuse of contact lenses to keep lenses clean and free from contaminantsincluding potentially harmful bacteria and fungi. A variety ofdisinfecting compositions for contact lenses are known. Hydrogenperoxide systems, in particular, 3% hydrogen peroxide, are in commonuse. Hydrogen peroxide is strongly biocidal and also is a strongoxidizing agent which positively impacts cleaning. However, hydrogenperoxide at the 3% level is also toxic to the eye, and therefore thehigh levels of hydrogen peroxide used to achieve disinfection must bedecomposed to water and oxygen before the lens is safe to reinsert intothe eye. This process is known as neutralization or inactivation.Typically, contact lens disinfection systems employ either an enzymiccatalyst such as catalase or a metal-based catalyst such as platinum toeffect neutralization. A typical disinfection process involves placing acontact lens into a hydrogen-peroxide containing disinfecting solutionfor a certain period of time, thereby achieving disinfection, followedby a neutralization period whereby the hydrogen peroxide is decomposed,typically by employing a catalytic agent.

Various additional agents may be added to the peroxide solutions toimprove cleaning and/or disinfection. For example, surface-active agentsmay enhance the cleaning or disinfecting properties of the solution.However, these types of agents may also lead to excessive foaming as gasis released during neutralization.

To help ensure that the disinfection is adequate, rubbing and rinsingsteps are also frequently recommended. However, these are additionalsteps that some consumers may not always perform consistently, and sothere has been an ongoing effort to design disinfecting systems that donot require the user to perform additional steps such as rubbing orrinsing.

Contact lenses may be broadly divided into two categories, rigidgas-permeable lenses, and soft, hydrogel lenses, although hybrids andother types of lenses exist. Soft or hydrogel lenses have become popularin part because they are comfortable to wear and do not require a periodof adaptation. Hydrogels are water swollen three-dimensional polymericnetworks that are used in a variety of biomedical applications includingdrug delivery agents, prosthetic devices and contact lenses. It is wellestablished that the surface characteristics of hydrogels are determinedby the orientation of hydrophobic and hydrophilic moieties of themacromolecules. See, e.g., Ketelson et al., Colloids and Surfaces B:Biointerfaces, Vol. 40, pages 1-9 (2005).

Because contact lenses are in intimate contact with the corneal surfaceand the human tear film, which is composed mainly of proteins, lipids,inorganic cations (e.g., calcium) and mucin, the biocompatibilitycharacteristics of the lenses are directly affected by the surfacewettability properties of the hydrogel materials, from which the lensesare formed. In particular, evaluating the surface wettability propertiesof a lens material is important because such properties affect thestability of the tear film. To maintain a stable tear film, a contactlens material must have hydrophilic surface properties. If the contactlens material becomes hydrophobic, the tear film may be disrupted. Todetermine the wettability of a surface via an aqueous solution, such ashuman lacrimal fluid, i.e., tears, the contact angle is measured. Thespreading of an aqueous fluid on a surface indicates that the surface ishydrophilic, thereby resulting in a low contact angle. The surface ishydrophobic if a drop of aqueous fluid does not spread, therebyresulting in a high contact angle.

A new family of contact lens materials, silicone hydrogels (“SiH”), isgradually replacing traditional hydrogels as the material of choice forextended wear soft contact lenses. Silicone hydrogel materials havesignificantly higher oxygen permeability than traditional soft lenshydrogels due to the presence of siloxane functional groups.Additionally, the presence of siloxane groups in SiH materials resultsin a lens surface having hydrophobic properties. An example of a SiHlens is the Acuvue Advance® contact lenses marketed by Johnson &Johnson.

Various techniques, for example, plasma surface treatments andincorporation of molecules within the lens material, have been utilizedin order to provide a biocompatible, hydrophilic and wettable lenssurface. Although modifying the surface can improve biocompatibility, ithas also been reported that some silicone hydrogel materials accumulatelipids over time, and that this build-up may result in a decrease in thewettability of the silicone hydrogel lens material and surface.

The wettability characteristics of the surfaces of contact lenses mayalso be modified by reducing the amount of hydrophobization on thesurfaces. Surfactants have been utilized in prior compositions fortreating contact lenses, for example poloxamers and poloxamines, such asthe Pluronic® and Tetronic® brands of surfactants, which arepoly(oxyethylene)-poly(oxypropylene) (“PEO-PPO”) block copolymers, havebeen used extensively in prior products utilized to treat contactlenses. However, such surfactants do not wet SiH lenses efficiently.

U.S. Pat. No. 5,423,012 (Winterton et al.) discloses buffered peroxideformulations with poloxamine or poloxamer surface active agents.

U.S. Pat. No. 5,746,972 (Park et al.) discloses compositions containinghydrogen peroxide and a solid ethylene oxide/propylene oxide blockcopolymer surfactant having at least 70% by weight polyethylene oxide.

U.S. Pat. No. 7,022,654 (Tsao) discloses compositions containinghydrogen peroxide and hydrophobe-hydrophile block copolymers where thehydrophile component constitutes less than 50 weight percent of theblock copolymer.

A new class of surface-active agents has been found to efficiently wetSiH lenses, namely, EO-BO copolymers. However, it has been found thatEO-BO copolymers may cause excessive foaming when used in peroxide-baseddisinfecting solutions during neutralization, for example, with platinumcatalyst discs.

U.S. Patent Application Publication No. 2008/0138310 (Ketelson et al.)is discloses the use of poly(oxyethylene)-poly(oxybutylene) blockcopolymers in pharmaceutical compositions.

In view of the foregoing, there is a need for new methods andcompositions for improving the wettability of (SiH) contact lenses aswell as older lens types while minimizing foaming of peroxide-basedcontact lens disinfection formulations.

SUMMARY OF THE INVENTION

The present invention is directed to the use of block copolymersreferred to as (polyoxybutylene)-(polyoxyethylene)-(polyoxybutylene)block copolymers (“PBO-PEO-PBO”) to modify the surface properties ofophthalmic medical devices, so as to enhance the wettability of thedevices, and facilitate cleaning of the devices. The PBO-PEO-PBO blockcopolymers described herein may be contained in various types ofcompositions for treating medical devices, such as wetting solutions,soaking solutions, cleaning and comfort solutions, and disinfectionsolutions. The primary function of the PBO-PEO-PBO block copolymers inthe compositions of the present invention is to treat the surface of amedical device, particularly an ophthalmic device, such as a contactlens or an intraocular lens. Such treatment facilitates the wettabilityof the device and/or the cleaning of the device. This surface treatmenthas been found to be particularly effective relative to enhancing thewettability of SiH contact lenses. The present invention is based on anew finding that certain PBO-PEO-PBO block copolymers can be used withperoxide-based contact lens formulations to effectively modify contactlens surface properties at low concentrations, for example, improvingthe wetting properties of SiH contact lenses, without causing excessivefoaming during platinum-induced neutralization.

Wettability may be determined by measuring the contact angle, θ, fromthe Young-Dupré equation as follows:

γ_(LV) cos θ=γ_(SV)−γ_(SL)

where γ is the interfacial tension between two phases indicated by thesubscripts (S: solid, L: liquid, and V: vapor). Increasing γ_(SL) and/orγ_(LV) increases the contact angle θ. For example, a water droplet beadsup on a hydrophobic surface, displaying high contact angle at thewater-solid interface (e.g. a contact lens surface soaked in saline).Water spreads out over a hydrophilic surface, displaying low contactangles (e.g. a contact lens soaked in a surfactant solution).

When a surfactant is present in a peroxide solution, foaming may occurdue to the release of oxygen from the neutralization effect of theperoxide with the catalyst. The volume of foam can be substantial andwhen the amount of foaming is excessive the foaming may interfere withthe procedures necessary to effectively disinfect a contact lens, forexample, when the volume of foam exceeds the dimensions of the containerused.

In one embodiment the present invention is directed to a compositioncomprising an effective amount of at least onepoly(oxybutylene)-poly(oxyethylene)-poly(oxybutylene) block copolymerhaving a molecular weight in the range of 500 to 10,000 Daltons, wherebythe composition, when combined with a peroxide disinfecting solution,does not cause excessive foaming upon neutralization.

In another embodiment, the present invention is directed to anophthalmic composition for disinfecting contact lenses comprising aneffective amount of at least onepoly(oxybutylene)-poly(oxyethylene)-poly(oxybutylene) block copolymerhaving a molecular weight in the range of 500 to 12,000 Daltons and adisinfecting amount of peroxide and an ophthalmically acceptable vehicletherefor.

In another embodiment the present invention is directed to a method ofimproving the wetting properties of a peroxide-based contact lensdisinfection composition, said method comprising adding to a compositioncomprising peroxide and a poly(oxyethylene)-poly(oxypropylene) blockcopolymer an effective amount of apoly(oxybutylene)-poly(oxyethylene)-poly(oxybutylene) block copolymer.

The present invention is more fully discussed with the aid of thefollowing figures and detailed description below.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph of contact angle measurements for selected PBO-PEO-PBOcopolymers.

FIG. 2 is a graph of contact angle measurements for compositionscontaining varying amounts of BO₃EO₄₅BO₃, BO₃EO₁₈₂BO₃, and Pluronic17R4.

DETAILED DESCRIPTION OF INVENTION

As utilized herein, the following abbreviations and terms, unlessotherwise indicated, shall be understood to have the following meanings:

The abbreviation “SiH” means silicone hydrogel.

The abbreviation “PEO-PPO” means poly(oxyethylene)-poly(oxypropylene).

The abbreviation “PBO-PEO-PBO” meanspoly(oxybutylene)-poly(oxyethylene)-poly(oxybutylene).

The abbreviation “PHMB” means polyhexamethylene biguanide.

The abbreviation “mOsm/kg” means milliosmoles/kilogram of water.

The abbreviation “pHEMA” means poly(2-hydroxyethyl methacrylate).

The abbreviation “HLB” means hydrophilic-lipophilic balance.

The abbreviation “EO” means oxyethylene.

The abbreviation “BO” means oxybutylene.

The term “contact angle” is a quantitative measure of the wetting of asolid by a liquid and defined geometrically as the angle formed by aliquid where liquid, gas and solid phases intersect. Alternative,related terms that may be used herein include “wetting angle” or“advancing contact angle.”

The term “hydrophilic” means having a strong affinity for water.Alternative, related terms that may be used herein include“hydrophilicity”.

The term “hydrophobic” means having little or no affinity for water.Alternative, related terms that may be used herein include,“hydrophobicity”.

The term “pHEMA-MAA” means contact lenses comprised ofpoly(2-hydroxyethyl methacrylate-co-methacrylic acid). ExemplarypHEMA-MAA lenses include “Acuvue® 2” (Johnson & Johnson).

The term “surfactant” means a substance capable of reducing the surfacetension of a liquid, e.g., water or an aqueous solution, in which thesubstance is dissolved.

The term “wetting” means converting a hydrophobic surface whereon aliquid (e.g., water) does not spread because the liquid has an increasedsurface tension to a surface that is hydrophilic whereon the liquidspreads readily because its surface tension is reduced, as determined bya contact angle experiment. Alternative, related terms that may be usedherein include “wettability”.

The term “uptake” refers to the amount of surfactant that is absorbedand/or adsorbed by a contact lens or other medical device. Alternativeterms that may be used herein include, “uptake concentration”,“surfactant uptake”, “uptake results”, “uptake data” and “uptakeconcentration of surfactants”.

The term “oxyethylene” means a two carbon alkylenyl group bonded to anoxygen atom, for example —CH₂—CH₂O—.

The term “oxybutylene” means a four carbon alkenyl group bonded to anoxygen atom, for example, —[OCH₂C(CH₂CH₃)H]—.

The term “block copolymer” is a polymer that has at least onehomopolymeric chain of one monomer and at least one additionalhomopolymeric chain of a second monomer. Exemplary configurations ofsuch block copolymers include branched, star, di-block, tri-block and soon.

The term “homopolymer” means a polymer formed from a single monomer; forexample, polyethylene formed by polymerization of ethylene.

The term “an amount effective to disinfect” means an amount of adisinfecting agent effective in producing the desired effect ofdisinfecting contact lenses by substantially reducing the number ofviable microorganisms present on the lenses, preferably an amount which,either singly or in combination with one or more additional disinfectingagents, is sufficient.

The term “an amount effective to clean” means an amount of a cleaningagent that facilitates removing, and is preferably effective to remove,debris or deposit material from a contact lens contacted with thecleaning agent containing composition.

The term “an amount effective to enhance wettability” means an amount ofto wetting agent that reduces the contact angle of a contact lens.

The term “effective amount”, when not otherwise qualified, means anamount effective to enhance the wettability of a surface such as acontact lens without causing excessive foaming, for example, duringneutralization of peroxide in a peroxide-based contact lens disinfectingcomposition.

The term “excessive foaming” means an amount of foaming that wouldinterfere with one or more of the steps needed to ensure effectivedisinfection, for example, when the volume of foam exceeds thedimensions of the container used for disinfection.

The term “ophthalmically acceptable vehicle” means a pharmaceuticalcomposition having physical properties (e.g., pH and/or osmolality) thatare physiologically compatible with ophthalmic tissues.

The block copolymers utilized in the present invention comprisecompounds that contain hydrophilic and hydrophobic segments that can bealtered to control the HLB (hydrophilic-lipophilic balance), molecularweight and other properties of the block copolymers using well knownanionic polymerization techniques. More particularly, the blockcopolymers of the present invention are those that include apoly(oxyethylene) block as the hydrophilic component and twopoly(oxybutylene) blocks as the hydrophobic component and are in theform of a tri-block copolymer. These copolymers may also be described interms of the approximate or average value assigned to the respectiverepeating group, for example, (BO)₃(EO)₆₀(BO)₃, where the average valueof the oxyethylene group is 60, and the average value of the oxybutylenegroups is 3.

Preferred polymers of the present invention are tri-block copolymers ofthe following general formula:

(BO)_(n)(EO)_(m)(BO)_(n)  (I)

wherein m is an integer having an average value of 5 to 1000 and n is aninteger having an average value of 2 to 100; more preferably, m has anaverage value of 9 to 182 and n has an average value of 3 to 21; mostpreferably, m ranges from 45 to 182 and n has an average value of 2 to4.

PBO-PEO-PBO tri-block copolymers of the following general formula arepreferred:

wherein R is independently selected from the group consisting ofhydrogen, methyl, ethyl, propyl and butyl; m is an integer having anaverage value of 10 to 1000; and n is an integer having an average valueof 2 to 4.

PBO-PEO-PBO tri-block copolymers of the formula (II) wherein n has anaverage value of 3 are particularly preferred.

Most preferred is a copolymer of formula (II) wherein one of end group Ris hydrogen; m has an average value selected from the group consistingof 45, 90 and 182; and n has an average value of 3.

The PBO-PEO-PBO block copolymers utilized in the present invention havea molecular weight in the range of 500 to about 10,000 Daltons; and morepreferably in the range of 800 to about 9,000 Daltons.

Maintaining a proper hydrophilic-lipophilic balance (HLB) impartscertain to properties to the PBO-PEO-PBO block copolymer compositions ofthe present invention. For example, the HLB of the block copolymersutilized in the compositions of the present invention is directlyrelated to the solubility, surface wettability, and interfacial surfaceactivity properties of the compositions of the present invention.

The BO portion of the block copolymer of formula (I) is hydrophobic andis primarily responsible for the wettability properties of thecompositions described herein. The EO portion of the copolymer providesthe compositions with hydrophilic properties, but more importantly, itis this portion of the co-polymer that determines the aqueous solubilityof the copolymers. Although it is possible to utilize solubilizingagents in the compositions of the present invention, in which case theratio of the length EO to BO segments is somewhat less critical, it ispreferred to utilize copolymers that do not require solubilizing agents,as such compounds may disrupt or modify the HLB, which in turn mayadversely affect the wettability properties of the compositions, causeocular irritation, or create other concerns.

The foregoing PBO-PEO-PBO block copolymers may be prepared by theapplication or adaptation of known methods described in the literature,for example, as described in Yang, Z.; Pickard, S.; Deng, N.-J.; Barlow,R. J.; Attwood, D.; Booth, C. Macromolecules 1994, 27, 2371-2379; Yang,Y.-W.; Yang, Z.; Zhou, Z.-K.; Attwood, D.; Booth, C. Macromolecules1996, 29, 670-680; Liu, T.; Zhou, Z.; Wu C.; Chu B.; Schneider, a K.;Nace, V. M., J. Phys. Chem. B. 1997, 101, 8808-8815; and Nace, V. M., inNonionic Surfactants: Polyoxyalkylenc Block Copolymers, 1996, Chapter 1,1-30, the entire contents of each of which are hereby incorporated inthe present specification by reference. The foregoing PBO-PEO-PBO blockcopolymers may also be prepared by the application or adaptation ofknown methods described in U.S. Pat. Nos. 2,828,345 (Spriggs), and4,902,834 (Often et al.), the entire contents of each of which arehereby incorporated into the present specification by reference.

The PBO-PEO-PBO block copolymers described above may be synthesizedusing a well defined polyethylene glycol (PEG) polymer by controlledaddition of oxybutylene to the primary hydroxyl groups of the PEGpolymer. For example, the PBO-PEO-PBO tri-block copolymer(BO)_(n)(EO)_(m)(BO)_(n) may be prepared by sequential anionicpolymerization of ethylene oxide and butylene oxide according to thefollowing general reaction scheme:

The tri-block copolymers of the present invention may be characterizedaccording to known techniques, for example, gel permeationchromatography (GPC) and nuclear magnetic resonance spectroscopy (NMR).

The PBO-PEO-PBO block copolymers of the present invention may have freehydroxyl end groups, or, alternatively, one or both of the block endgroups may be “capped”, for example, with an alkyl group, preferably amethyl, ethyl, propyl or butyl group.

The PBO-PEO-PBO block copolymers of the present invention may also befunctionalized with reactive end groups for specific surface reactionsto covalently bind the polymer to a surface or prepare a new polymermaterial. The PBO-PEO-PBO block copolymers that may be utilized in thepresent invention are not limited relative to structure or molecularweight, so long as the block copolymers are soluble in aqueous solutionsand are non-toxic to ophthalmic tissue at concentrations on the order ofthose described herein.

The amount of PBO-PEO-PBO block copolymer required in the compositionsof the present invention may vary depending on the particular blockcopolymer selected and the particular purpose or function for which theblock copolymer is being utilized (e.g., contact lens wetting, contactlens cleaning and/or inhibition of uptake of lipids or otherbiomolecules), as well as on other variables, such as the identity andphysical properties of other components in the compositions. Thedetermination of the ideal concentration of a particular copolymer in agiven composition can be determined through routine testing. Suchconcentrations are referred to herein by means of the function to beperformed by the PBO-PEO-PBO block copolymers, such as, “an amounteffective to clean”, “an amount effective to enhance wettability”, “anamount effective to inhibit the uptake of biomolecules”, and so on. Whennot otherwise qualified, the term “effective amount” refers to an amounteffective to enhance the wettability of a contact lens without causingexcessive foaming during neutralization of peroxide in a peroxide-basedcontact lens disinfecting composition.

The total amount of PBO-PEO-PBO block copolymers contained in thecompositions of the present invention will typically be in the range of0.001 to about 1 weight/volume percent (“w/v %”), preferably about 0.05to 0.5 w/v %, more preferably between about 0.1 to 0.3 w/v %, mostpreferably about 0.2 w/v %.

The above-described block copolymers and variations thereof may be usedin combination, either with each other, or with other types of polymers.For example, PBO-PEO-PBO block copolymers or variations thereof may beused in combination with nonionic surfactants (e.g., poloxamer andpoloxamine block copolymers, such as the Tetronic® brand of surfactantsavailable from BASF) to provide additive or synergistic effects whereappropriate.

The compositions may also contain one or morepoly(oxyethylene)-poly(oxypropylene) block copolymers such as poloxameror poloxamine copolymers (e.g., poloxamine 1304, which is commerciallyavailable as “Tetronic® 1304”). Poloxamines, also known by the tradename Tetronic™, are tetrafunctional block copolymers which contain fourpolyethylene oxide (PEO)-polypropylene oxide (PPO) chains joined to thenitrogen atoms of a central ethylene diamine moiety. Poloxamers, alsoknown by the trade name Pluronic™, are nonionic block copolymerscomposed of a central hydrophobic chain of poly(oxypropylene) flanked bytwo hydrophilic chains of poly(oxyethylene). In a preferred embodiment,the PBO-PEO-PBO block polymers of the present invention are used incombination with poloxamer block copolymers. A particularly preferredembodiment of the present invention is a composition comprising a blockcopolymer of the formula

and poloxamer Pluronic 1784, a difunctional block copolymer availablecommercially (BASF Corporation, Mount Olive, N.J.), which may berepresented by the formula

One or more of the above-described poly(oxyethylene)-poly(oxypropylene)block copolymers may be contained in the compositions of the presentinvention in an amount effective to facilitate wetting and/or cleaningof contact lenses, which is referred to herein as an “effective amount”.Such amount will typically be in the range of 0.001 to about 1weight/volume percent (“w/v %”), preferably about 0.01 to 0.5 w/v %.

The block copolymers of the present invention may also be combined withother components commonly utilized in products for treating contactlenses, such as rheology modifiers, enzymes, antimicrobial agents,surfactants, chelating agents, buffering agents or combinations thereof.

A variety of buffering agents may be utilized in the compositions of thepresent invention, such as basic acetates, phosphates, boric acid,sodium borates, sodium citrates, citric acid, nitrates, sulfates,lactates, carbonates, bicarbonates, and combinations thereof. Buffers,when present, may be used in a concentration range of 0.001% to 2%, tomaintain the composition at a pH range of about 4 to about 9. Borate andpolyol systems may also be used to provide buffering, to enhanceantimicrobial activity, or to provide both buffering and an enhancementof antimicrobial activity, or other useful properties to thecompositions of the invention. The borate and polyol systems which maybe used include those described in U.S. Pat. Nos. 6,849,253; 6,503,497;6365,636; 6,143,799; 5,811,466; 5,505,953; and 5,342,620; the entirecontents of each are hereby incorporated in the present specification byreference.

Stabilizing agents may also be included in the compositions of thepresent invention, in order to control the rate of decomposition ofperoxide. Various types of stabilizing agents may be used, however,preferred stabilizing agents are those based on diethylenetriaminepenta(methylene phosphonic acid), for example, Dequest® 2060s (ThermphosUSA Corp., Anniston Ala.).

The present invention may be better understood by reference to thefollowing examples, which are provided to further illustrate certainpreferred embodiments of the invention, and should in no way beconstrued as limiting the scope of the invention. In the followingexamples, various methods known to one skilled in the art may beemployed to measure the contact angle for lenses according to thepresent invention. Exemplary methods include, but are not limited to,the Sessile method or the Captive Bubble method, as described in U.S.Patent Application Publication No. 2008/0138310 (Ketelson et al.), theentire contents of which is hereby incorporated into the presentspecification by reference.

Example 1

A series of PBO-PEO-PBO copolymers were investigated for foaming andwettability studies. Block lengths were confirmed by NMR. The BO unitswere fixed at 3 and 6 units with EO units ranging from 9 to 182. Theincrease in EO is to provide improved wettability, measured throughContact Angle, without sacrificing increased foaming, measured byvisualization of foaming during neutralization. The Molecular Weight(Mw), confirmed by GPC, ranged from 830 g/mol up to 8442/mol.

TABLE 1 Investigation of a series of PBO-PEO-PBO copolymers for foamingand wettability. Investigated Investigated Component M_(w) FoamingWettability BO₃EO₉BO₃ 830 ✓ ✓ BO₃EO₁₄BO₃ 1050 ✓ ✓ BO₃EO₂₂BO₃ 1402 ✓ ✓BO₃EO₄₅BO₃ 2414 ✓ ✓ BO₃EO₉₀BO₃ 4394 ✓ ✓ BO₃EO₁₃₆BO₃ 6418 ✓ — BO₃EO₁₈₂BO₃8442 ✓ ✓ BO₆EO₉BO₆ 1262 ✓ — BO₆EO₁₄BO₆ 1482 ✓ — BO₆EO₂₂BO₆ 1834 ✓ —BO₆EO₄₅BO₆ 2846 ✓ — BO₆EO₉₀BO₆ 4824 ✓ —A step-wise experimental testing procedure was followed, whereby thePBO-PEO-PBO copolymers were first tested for excessive foaming, and thenthose PBO-PEO-PBO copolymers that did not cause excessive foaming weretested for wettability by investigating their contact angles. Thecommercially-available peroxide formula Clear Care® (CibaVision, DuluthGA), which contains 0.02% Pluronic 17R4, modified by the addition of0.2% PBO-PEO-PBO, EO₄₅BO₁₁ and Tetronic 1304, was used to test forfoaming. While the container used to evaluate foaming can vary, in theexperiments described below AOSEPT Disposable Cup and Disc kits(CibaVision, Duluth GA), which hold approximately 20 mL of fluid, wereused. To a new cup 10 mL of peroxide formulation was added. This wasthen capped and tightened with the platinum cartridge. The peroxideformulations where visually inspected at the beginning andintermittently (every 10 minutes) for foaming. Excessive foaming wasconsidered to occur if solution leaked from the case. As indicated inTable 2, BO₆EO₉BO₆ through ₉₀BO₆, EO₄₅BO₁₁ and Tetronic 1304 all foamedexcessively in the modified Clear Care® formulation, while BO₃EO₉BO₃through BO₃EO₉BO₃ did not foam excessively in the modified Clear Care®formulation. These copolymers were then used to investigate ContactAngle for silicone hydrogel lenses following a procedure described inExample 2.

TABLE 2 Results of investigation of foaming. Surfactant added Foamingupon Investigated to Clear Care M_(w) Neutralization Contact AngleBO₃EO₉BO₃ 830 — ✓ BO₃EO₁₄BO₃ 1050 — ✓ BO₃EO₂₂BO₃ 1402 — ✓ BO₃EO₄₅BO₃2414 — ✓ BO₃EO₉₀BO₃ 4394 — ✓ BO₆EO₉BO₆ 1262 Excessive foaming —BO₆EO₁₄BO₆ 1482 Excessive foaming — BO₆EO₂₂BO₆ 1834 Excessive foaming —BO₆EO₄₅BO₆ 2846 Excessive foaming — BO₆EO₉₀BO₆ 4824 Excessive foaming —EO₄₅BO₁₁ 2920 Excessive foaming — Tetronic 1304 10500 Excessive foaming—

Example 2

The contact angles for two silicone hydrogel lenses, AcuVue Oasys® (AO)(Johnson & Johnson Vision Care, Inc., Jacksonville Fla.) and PureVision® (PV) (Bausch & Lomb Inc., Rochester, N.Y.), were measured asdescribed below. The results are reported in FIG. 1, which shows ContactAngle values after a 3^(rd) rinse cycle in Unisol® preservative-freesaline solution (Alcon Laboratories, Inc. Fort Worth, Tex.) for PureVision and Acuvue Oasys contact lenses in Clear Care® formulationsmodified with the addition of 0.2% PBO-PEO-PBO. Clear Care® was thecontrol for both PV and AO lenses.

Contact Angle Measurements for Control Lenses: No Pre-Soaking

Two brands of silicone hydrogel contact lenses (AcuVue Oasys® and PureVision®), were soaked in Unisol® saline solution overnight to removeresidual packing solution contaminants, prior to measuring the contactangles. The lenses were then pre-soaked for 24 hours in Unisol with 0.2%PBO-PEO-PBO. The contact angle of each lens was then measured accordingto the Sessile drop method, as described below, at room temperature,i.e, 23° C.±0.5. Contact angle measurements for the control lenses didnot include a pre-soaking step.

Sessile Drop Method

A video based contact angle measuring system (OCA 20) from FutureDigital Scientific employing SCA20 software (Version 2.1.5 build16) wasused. An accelerated approach was developed to evaluate the lens surfacewettability over a specific time period. The lenses were subjected tosequential wetting and air exposure cycles to simulate the clinicalcontact lens wetting and drying conditions that occur during the normalblinking process. One “cycle” means that a lens was soaked in salinesolution for 5 minutes, followed by an exposure of the lens to air for1.5 minutes. The contact angles of a water droplet on the lens surfacewere measured within 10 seconds following each cycle. In allmeasurements, the left and right contact angles were determined and themean of these contact angles was used. For each drop image, threeindependent fitting measurements were performed to provide three meancontact angles of the same drop image. The average of these threecontact angles was determined and the precision was within ±3%.

The steps of a typical experimental protocol are described as follows:

-   -   1) Add 10 mL of UNISOL 4 to a 20 mL scintillation vial.    -   2) Take one lens from the blister pack and dab dry with lens        tissue paper.    -   3) Place lens in 20 mL scintillation vial with UNISOL 4 and soak        for 24 hours.    -   4) Take UNISOL 4® soaked lens and place in a new AOSEPT lens        container. Add 10 mL of test solution (or Clear Care).        Neutralize the solution for 24 hours.    -   5) Remove lens from the neutralized solution in the Aosept        cartridge and place on lens mold stand.    -   6) After 90 seconds exposed in air, drop 54 of deionized water        on lens and is quickly take picture for a Contact angle        measurement.    -   7) Place in a new 20 mL scintillation vial with 10 mL of UNISOL        4®. Allow to sit for 5 minutes.    -   8) Measure Contact Angle of lenses at least to 3rd rinse cycle.        (Includes 90 seconds in air followed by 5 minute soak in fresh        10 mL of Unisol 4®).

PV lenses were soaked in Clear Care® modified with 0.2% PBO-PEO-PBOusing the non-foaming copolymers from Table 2. Two modified Clear Care®peroxide solutions with PBO-PEO-PBO with low contact angles, BO₃EO₄₅BO₃and BO₃EO₉₀BO₃, were investigated with AO lenses.

As can be seen from the data as shown in FIG. 1, PBO-PEO-PBO in aperoxide formulation improves the wettability of the PV and AO lenses.

Example 3

A series of formulations consisting of 3.5% Peroxide, 0.75% SodiumBorate, 0.35% Boric Acid at pH of 7.9 after neutralization were preparedwith selected surfactants. The PBO-PEO-PBO surfactants were added incombination with Pluronic 17R4 to investigate their combined foaming andwettability.

TABLE 3 PBO-PEO-PBO's and Pluronic 17R4 investigated for foaming andwettability studies using borate buffered vehicle. Investigated FoamingUpon Investigated Component M_(w) Neutralization Contact AngleBO₃EO₄₅BO₃ 2414 ✓ ✓ BO₃EO₉₀BO₃ 4394 ✓ — BO₃EO₁₃₆BO₃ 6418 ✓ — BO₃EO₁₈₂BO₃8442 ✓ ✓ Pluronic 17R4 2650 ✓ ✓None of the borate buffered peroxide formulations using thePBO-PEO-PBO's in Table 3 foamed in the presence of PLURONIC 17R4 uponneutralization.

Example 4

TABLE 4 PBO-PEO-PBO and Pluronic 17R4 Borate Buffered formulations. Comp(% wt/% wt) A B C D E F G H CC Pluronic 17R4 0.02 0.02 — — 0.02 0.02 — —(0.02) BO₃EO₄₅BO₃ 0.02 0.2 0.02 0.2 — — — — — BO₃EO₉₀BO₃ — — — — 0.020.2 0.02 0.2 — Na₂B₄O₇ × 10H₂O 0.75 0.75 0.75 0.75 0.75 0.75 0.75 0.75 —Boric Acid 0.35 0.35 0.35 0.35 0.35 0.35 0.35 0.35 — NaH₂PO₄ 0.136 0.1360.136 0.136 0.136 0.136 0.136 0.136 — Na₂HPO₄ 0.062 0.062 0.062 0.0620.062 0.062 0.062 0.062 — NaCl 0.23 0.23 0.23 0.23 0.23 0.23 0.23 0.23 —DEQUEST 2060S 0.12 0.12 0.12 0.12 0.12 0.12 0.12 0.12 — QS (100 mL of QSQS QS QS QS QS QS QS — PW) Hydrogen 3.5 3.5 3.5 3.5 3.5 3.5 3.5 3.5 —Peroxide Foaming upon — — — — — — — xs — Neutralization

TABLE 5 PBO-PEO-PBO and Pluronic 17R4 Borate Buffered formulations. Comp(% wt/% wt) I J K L M N O P CC Pluronic 17R4 0.02 0.02 — — 0.02 0.02 — —(0.02) BO₃EO₁₃₆BO₃ 0.02 0.2 0.02 0.2 — — — — — BO₃EO₁₈₂BO₃ — — — — 0.020.2 0.02 0.2 — Na₂B₄O₇ × 10H₂O 0.75 0.75 0.75 0.75 0.75 0.75 0.75 0.75 —Boric Acid 0.35 0.35 0.35 0.35 0.35 0.35 0.35 0.35 — NaH₂PO₄ 0.136 0.1360.136 0.136 0.136 0.136 0.136 0.136 — Na₂HPO₄ 0.062 0.062 0.062 0.0620.062 0.062 0.062 0.062 — NaCl 0.23 0.23 0.23 0.23 0.23 0.23 0.23 0.23 —DEQUEST 2060S 0.12 0.12 0.12 0.12 0.12 0.12 0.12 0.12 — QS (100 mL ofPW) QS QS QS QS QS QS QS QS — Hydrogen Peroxide 3.5 3.5 3.5 3.5 3.5 3.53.5 3.5 — Foaming upon — — xs xs — — xs xs — NeutralizationFrom Tables 4 and 5, the borate buffered peroxide formulations A-D, M, Nand O were used to investigate contact angle on two types of lenses,Pure Vision (PV) and Acuvue Oasys (AO). These formulations did not foamand were at the low and high end of the EO block lengths, 45 and 182 EOunits respectively. PV and AO historically have high Contact Angles,80°-110°, reflecting low wettability of lens.

TABLE 6 PBO-PEO-PBO and Pluronic 17R4 Borate Buffered formulations usedfor Contact Angle Measurements for PV and AO lenses. Comp (% wt/% wt) AB C D M N O CC Pluronic 17R4 0.02 0.02 — — 0.02 0.02 — (0.02) BO₃EO₄₅BO₃0.02 0.2 0.02 0.2 — — — — BO₃EO₁₈₂BO₃ — — — — 0.02 0.2 0.02 — Na₂B₄O₇ ×10H₂O 0.75 0.75 0.75 0.75 0.75 0.75 0.75 — Boric Acid 0.35 0.35 0.350.35 0.35 0.35 0.35 — NaH₂PO₄ 0.136 0.136 0.136 0.136 0.136 0.136 0.136— Na₂HPO₄ 0.062 0.062 0.062 0.062 0.062 0.062 0.062 — NaCl 0.23 0.230.23 0.23 0.23 0.23 0.23 — DEQUEST 2060S 0.12 0.12 0.12 0.12 0.12 0.120.12 — QS (100 mL of PW) QS QS QS QS QS QS QS — Hydrogen Peroxide 3.53.5 3.5 3.5 3.5 3.5 3.5 —

FIG. 2 shows the results of contact angles measured after the 3rd rinsecycle in UNISOL for Pure Vision lenses in Borate Buffered formulationswith PBO-PEO-PBO and with and without Pluronic 17R4. Clear Care® was thecontrol for the PV lenses.

Formulations B and N showed better wetting trend, with lower contactangles, than the control of Clear Care® for PV lens materials.Formulation B has 0.02% PLURONIC 17R4 and 0.2% BO₃EO₄₅BO₃, whileformulation N has 0.02% PLURONIC 17R4 and 0.2% BO₃EO₁₈₂BO₃.

1. An ophthalmic composition for disinfecting contact lenses comprisingan effective amount of at least onepoly(oxybutylene)-poly(oxyethylene)-poly(oxybutylene) block copolymerhaving a molecular weight in the range of 500 to 12,000 Daltons and adisinfecting amount of peroxide and an ophthalmically acceptable vehicletherefor.
 2. A composition according to claim 1, wherein thepoly(oxybutylene)-poly(oxyethylene)-poly(oxybutylene) block copolymer isof the formula (BO)_(n)(EO)_(m)(BO)_(n), wherein m is an integer havingan average value of 5 to 1000 and n is an integer having an averagevalue of 2 to
 100. 3. A composition according to claim 2, wherein thepoly(oxybutylene)-poly(oxyethylene)-poly(oxybutylene) block copolymer isof the formula (BO)_(n)(EO)_(m)(BO)_(n), wherein m is an integer havingan average value of 9 to 182 and n is an integer having an average valueof 3 to
 21. 4. A composition according to claim 2, wherein thepoly(oxybutylene)-poly(oxyethylene)-poly(oxybutylene) block copolymer isof the formula (BO)_(n)(EO)_(m)(BO)_(n), wherein m is an integer havingan average value of 5 to 1000 and n is an integer having an averagevalue of 2 to
 4. 5. A composition according to claim 4, wherein m rangesfrom 45 to
 182. 6. A composition according to claim 4, wherein theaverage value of m is selected from the group consisting of 45, 90 and182 and the average value of n is
 3. 7. A composition according claim 1,wherein the poly(oxybutylene)-poly(oxyethylene)-poly(oxybutylene) blockcopolymer is of the formula

wherein R is independently selected from the group consisting ofhydrogen, methyl, ethyl, propyl and butyl; m is an integer having anaverage value of 10 to 1000; and n is an integer having an average valueof 2 to
 4. 8. A composition according to claim 7, wherein R isindependently selected from the group consisting of methyl and hydrogen,and the average value of m is selected from the group consisting of 45,90 and 182, and the average value of n is
 3. 9. A composition accordingto claim 1, further comprising an effective amount of apoly(oxyethylene)-poly(oxypropylene) block copolymer.
 10. A compositionaccording to claim 9, wherein the poly(oxyethylene)-poly(oxypropylene)block copolymer is of the formula


11. A composition according to claim 1, wherein the solution containssaid block copolymer at a concentration of 0.001 to 1% w/v.
 12. Acomposition according to claim 1, wherein the ratio of m to n is in therange of 14:1 to 60:1.
 13. A composition comprising an effective amountof at least one poly(oxybutylene)-poly(oxyethylene)-poly(oxybutylene)block copolymer having a molecular weight in the range of 500 to 10,000Daltons, whereby the composition, when combined with a peroxidedisinfecting solution, does not cause excessive foaming uponneutralization.
 14. A method of improving the wetting properties of aperoxide-based contact lens disinfection composition, said methodcomprising adding to a composition comprising peroxide and apoly(oxyethylene)-poly(oxypropylene) block copolymer an effective amountof a poly(oxybutylene)-poly(oxyethylene)-poly(oxybutylene) blockcopolymer.
 15. A method of disinfecting a contact lens, said methodcomprising (a) contacting a contact lens with a composition according toany one of claims 1-13; and (b) neutralizing said hydrogen peroxide bycatalytic decomposition.